ABSTRACT Bacterially derived natural products have provided drug leads, inspired chemists, and have improved our understanding of biology. The importance of both bacteria and the molecules they produce has become increasingly clear, especially as our understanding of the human microbiome continues to improve. Nonetheless, the discovery of new molecules as potential therapeutics has been negatively impacted by the problem of rediscovery. Additionally, whole genome sequencing efforts have revealed that only a fraction of the biosynthetic potentials found in bacterial genomes has been realized in the lab. Taken together, these observations make clear two critical barriers: 1. rediscovery of known molecules obscures new molecule discovery; and 2. many biosynthetic clusters remain dormant/silent in the laboratory setting. This project aims to overcome these barriers by developing innovative analytical strategies to drive discovery. At the same time interspecies interactions will be leveraged to activate biosynthetic gene clusters that are typically silenced under laboratory conditions. The potential impact of this proposal entails the discovery of new molecules with therapeutic potentials as well as a greater understanding of bacterial interactions that modulate small molecule production. Further, we aim to take advantage of our recent discovery that modulators of quorum sensing activate biosynthetic gene clusters in actinomycetes. To achieve these goals, we have devised three specific aims targeting the two defined critical barriers.